rules and guidance for pharmaceutical manufacturers distributors 2015 - the green guide

The Application and Inspection Process “What to Expect”

Applicants for a new wholesale dealer’s licence (WDA(H)) or existinglicence holders wishing to vary their licence should apply using the MHRAProcess Licensing Portal accessible via the MHRAwebsite.1

MHRA acting as the licensing authority will only issue a wholesaledealer’s licence when it is satisfied, following an inspection of the site(s),that the information contained in the application is accurate and incompliance with the requirements of the legislation.When appropriate, MHRA may refuse to grant a wholesale dealer’s

licence or may grant a wholesale dealer’s licence otherwise than as appliedfor. In such cases the licensing authority will notify the applicant of itsproposals. The notification will set out the reasons for its proposals andgive the applicant a period of not less than 28 days to respond.

Planning

Fee bearing inspections of licensed wholesale dealers are carried out toassess the degree of compliance to standards of Good Distribution Practice(GDP) and compliance with the provisions of the licence.

Qualification of Customers andSuppliers 112

Qualification of suppliers 113Compliance with GDP 113Routine re-qualification 114Due diligence 114Falsified Medicines 114Regulatory Action 116Diverted Medicines 116Parallel Distribution 116Relabelling/Repackaging 118Maintenance of the integrity of thesupply chain 118

Continued Supply 119

Reporting Adverse Reactions 121Product Recall/Withdrawal 121Issue a “Recall” 122Issue a “Drug Alert” 122Management of the recall 123Management of Recall Activity by

Wholesalers 123Management of Recall Activity by

Brokers 124Supply and brokering to countriesoutside of the UK 124

Testing the recall process 125Follow-up action 126Reporting a suspected defect 126

1 http://www.mhra.gov.uk/Howweregulate/Medicines/Licensingofmedicines/

Informationforlicenceapplicants/Licenceapplicationforms/Wholesaledealersli-

cencesapplicationforms/index.htm

82 GUIDANCE ON WHOLESALE DISTRIBUTION PRACTICE AND BROKERING

Sample pages from The Green Guide

Inspections of wholesaler dealers (WDA(H) holders) are undertaken aspart of the risk-based inspection programme, further details of which canbe found in another section of this guide.

Notification

Advance notice of inspection is normally given to a company, unlesscircumstances require that an unannounced inspection should take place.The timing of the inspection would normally be notified in writing by theinspector.In accordance with the GDP risk-based inspection process, sites will be

required to complete a Compliance Report in advance of inspection.Further information and guidance can be found in our risk-basedinspections section.

Conduct

The major stages of the inspection process are:

l the introductory or opening meetingl the detailed site inspectionl the summary or closing meeting

Introductory or opening meeting

The purpose of the meeting is for the Inspector to meet with theappropriate key personnel from the company to discuss the arrangementsfor the inspection. The Inspector would typically confirm the nature of thebusiness, premises and security arrangements, areas to be visited and anydocumentation which may be required.

Site inspection

The purpose of the site inspection is to determine the degree of conformityof the operations to the requirements of Good Distribution Practice and toassess compliance with the terms and conditions of licences issued underthe appropriate legislation or with details submitted in support of anapplication for a licence. The inspection will typically involve visits togoods receipt, storage and dispatch areas (including ambient andrefrigerated), returns/quarantine area, interviews with key personnel anda review of stock movement and quality system documentation includingproduct recalls. Any observations, recommendations and deficiencies noted

6 UK Guidance on Wholesale Distribution Practice 83

UK

GU

IDA

NC

EO

NW

HO

LES

ALE

DIS

TR

IBU

TIO

NP

RA

CT

ICE


during the inspection would normally be discussed with the companyrepresentatives at the time.During inspections of manufacturing and wholesale operations, samples

of starting materials, work in progress and finished products may be takenfor testing if an Inspector considers that this might assist in the detection ofquality deficiencies. Occasionally, samples may be taken when these cannotbe obtained from other sources, for routine surveillance purposes.

Summary or closing meeting

The purpose of the meeting is for the Inspector to provide the companywith a verbal summary of the inspection findings and to allow the companyto correct at this stage any misconceptions. The Inspector would typicallysummarise the definition and classification of deficiencies they propose toreport and the company are encouraged to give an undertaking to resolvethe deficiencies and to agree a provisional timetable for corrective action.The Inspector would also describe the arrangements for the formalnotification of the deficiencies to the company (the post-inspection letter)and what is expected as a response.Deficiencies are classified as follows:

l Critical deficiency:

Any departure from Guidelines on Good Distribution Practice resultingin a medicinal product causing a significant risk to the patient and publichealth. This includes an activity increasing the risk of falsified medicinesreaching the patients. A combination of a number of major deficienciesthat indicates a serious systems failure. An example of a critical deficiencycould be:Purchase from or supply of medicinal products to a non-authorised

person; Storage of products requiring refrigeration at ambient tempera-tures; Rejected or recalled products found in sellable stock.

l Major Deficiency:

A non-critical deficiency: which indicates a major deviation from GoodDistribution Practice; or which has caused or may cause a medicinalproduct not to comply with its marketing authorisation in particular itsstorage and transport conditions; or which indicates a major deviationfrom the terms and provisions of the wholesale distribution authorisation;or a combination of several other deficiencies, none of which on their ownmay be major, but which may together represent a major deficiency.



l Other Deficiency:

A deficiency which cannot be classified as either critical or major, butwhich indicates a departure from Guidelines on Good Distribution Practice.The choice of company representatives at the meeting is primarily for the

company to decide, but should normally include the senior staff who werepresent during the inspection and the Responsible Person (RP).Depending upon the inspection findings and the response from the

company during and following the inspection, the Inspector may take oneof a number of actions ranging from:

l issuing a GDP certificate confirming essential compliance with GDPl referral to the Compliance escalation process or the Inspection ActionGroup (IAG) for consideration for adverse licensing action where seriousnon-compliance is found.

Further information on the Compliance escalation process and IAG canbe found in this publication.

Company responses

The inspected site is expected to provide a written response (by letter oremail) to the post-inspection letter within the required timeframe. Theresponse should consider the context of the deficiency within the overallquality system rather than just the specific issue identified. The responseshould include proposals for dealing with the deficiencies, together with atimetable for their implementation. The response should be structured asfollows:

l Restate the deficiency number and the deficiency as written below.l State the proposed corrective action.l State the proposed target date for the completion of the corrective action(s).l Include any comment the company considers appropriate.l Provide evidence supporting any corrective action where it is consideredappropriate.

Inspection report

Once the Inspector is satisfied that any necessary remedial action has beentaken or is in hand and that the site is essentially in compliance with GDP,an inspection report and GDP certificate are finalised.


UK

GU

IDA

NC

EO

NW

HO

LES

ALE

DIS

TR

IBU

TIO

NP

RA

CT

ICE


Risk-based Inspection Programme

Introduction

MHRA has been incorporating elements of risk management into itsinspection programme for a number of years. A formal risk-based inspection(RBI) programme was implemented on 1 April 2009, following publicconsultation MLX 345. The RBI programme covers all aspects of goodpractices associated with the inspection of clinical, pre-clinical and qualitycontrol laboratories, clinical trials, manufacturers, wholesalers andpharmacovigilance systems. The primary aim of the RBI programme is toenable inspectorate resources to focus on areas that maximise protection ofpublic health while reducing the overall administrative and economicburden to stakeholders.

Sentinel risk information module

Working with technology partners Accenture, MHRA established itsSentinel IT system in 2005 which is used by most agency business areas tomanage business processes for:

l marketing authorisationsl pharmacovigilancel clinical trialsl manufacturer’s and wholesale dealer’s licencesl inspectionsl issuing GMP and GDP certificates and automatic loading of these intothe EMA’s EudraGMDP database.

In February 2013 a newly developed Sentinel risk information modulewas deployed to expand upon the paper-based RBI system initiated in 2009.The Risk Estimation Tool uses the intelligence data collected on regulated

companies, their respective sites and previous inspection results across allGxP areas to predict a risk score as “likely next inspection result”. This scoreis calculated for every site and can be interpreted as a weighted sum ofinspection findings. Companies/sites are ranked based on predicted risk andbusiness rules are applied to suggest a next inspection date.A planning step allows inspectors to accept or reject the suggested date

taking into account other information which may not be included in thestatistical calculation. For estimation of the risk score, the tool uses alogistic regression statistical model incorporating all data elements for allcompanies and sites. The model is fit (i.e. recomputed) monthly based onthe most recent data extracted from Sentinel. The Empirica algorithmsoftware was designed by Oracle Health Services to provide detailed



analysis of the risk information. MHRA first used Empirica software in2006 for pharmacovigilance signal detection and management.The model estimates the association between inspection findings and

other covariates (events) observed in data. The algorithm makes a globalestimate on how these events affect inspection score within a GxP and thenapplies this when these events are recorded in the future. As a result thosefactors which are statistically most relevant to risk will receive the highestweighting and this will be continuously updated as more events arerecorded. The model looks at events over a five year period but appliesgreater significance to more recent data.

Current implementation status

A number of aspects of the algorithm are being validated including;

l The risk scorel The weighting of inspection outcomesl The weighting of the risk eventsl The generation of proposed inspection dates from the risk scorel Inclusion of all appropriate risk events

The algorithm is being assessed on an individual GxP basis as well asacross the GxPs. The algorithm output is being compared against theexisting RBI processes within the GxPs. Until the algorithm has beensuccessfully validated the existing risk-based inspection schedulingprocesses will remain in place.

GDP risk-based inspection (RBI) programme

The GDP risk-based inspection process commenced for all wholesaledealer’s licence holders on 1 April 2009.

Compliance report

Sites will be required to complete a Compliance Report in advance ofinspection, this will be prompted by the inspector. Guidance to completingthe report can be found within the document. The Compliance Reportshould be returned to your inspector prior to the inspection.

Risk rating process

Inspectors use the inspection outputs along with a number of other factorsto identify a risk rating for the site, which equates to a future inspection


UK

GU

IDA

NC

EO

NW

HO

LES

ALE

DIS

TR

IBU

TIO

NP

RA

CT

ICE


frequency. As this process is not concluded until the inspection is closed therisk ratings will not be discussed at the closing meetings. However a copyof the full inspection report which includes the full risk rating rationale isprovided to sites once the inspection has been closed.Issue of a certificate of GDP compliance and/or support of the site on the

relevant licence is indication of meeting the minimum level of GDPcompliance. Risk ratings identify the degree of surveillance required withinthe licensing and inspection program. There is no intention that sites berated against each other as a result of risk ratings assigned byMHRA. Riskratings can change following inspection resulting in either increased ordecreased risk. Inspection risk ratings will not be published by MHRA.There will be no formal process of appeal against risk ratings and future

inspection frequency. However any rating that results in an increasedinspection frequency from the previous standard will be peer reviewedbefore conclusion by a GDP operationsmanager.MHRA does have a formalcomplaints process if sites wish to log an issue, however any concernsregarding the inspection process should be raised with the inspector.

Conditions of Holding a Wholesale Dealer’s Licence

The holder of a wholesale dealer’s licence must comply with certainconditions in relation to the wholesale distribution of medicinal products.These conditions are set out in regulations 43 – 45 of the HumanMedicinesRegulations 2012 [SI 2012/1916] (“the Regulations”). They require thatthe licence holder shall:

l comply with the guidelines on Good Distribution Practice (GDP);1

l ensure, within the limits of their responsibility as a distributor of medicinalproducts, the appropriate and continued supply of such medicinalproducts to pharmacies and persons who may lawfully sell such productsby retail or whomay lawfully supply them in circumstances correspondingto retail sale, so that the needs of patients in the UK are met;

l provide and maintain such staff, premises, equipment and facilities forthe handling, storage and distribution of the medicinal products underthe licence as are necessary to maintain the quality of, and ensure properdistribution of the medicinal products;

l inform the licensing authority of any proposed structural alteration to, ordiscontinued use of, premises to which the licence relates or premiseswhich have been approved by the licensing authority;

l inform the licensing authority of any change to the Responsible Person;

1 Guidelines on Good Distribution Practice of Medicinal Products for Human Use

(2013/C 343/01) http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:

C:2013:343:0001:0014:EN:PDF.



rules and guidance for pharmaceutical manufacturers distributors 2015 - the green guide

Education